Azaindoles as inhibitors of c-Jun N-terminal kinases

ABSTRACT

The present invention relates to novel 5-substituted 7-azaindole compounds of formula (I), their use in the inhibition of c-Jun N-terminal kinases, their use in medicine and particularly in the prevention and/or treatment of neurodegenerative disorders related to apoptosis and/or inflammation. The invention also provides processes for manufacture of said compounds, compositions containing them and processes for manufacturing such compositions

The present invention relates to novel 5-substituted 7-azaindolecompounds, their use in the inhibition of c-Jun N-terminal kinases,their use in medicine and particularly in the prevention and/ortreatment of neurodegenerative disorders related to apoptosis and/orinflammation. The invention also provides processes for manufacture ofsaid compounds, compositions containing them and processes formanufacturing such compositions.

c-Jun N-terminal kinases (hereinafter referred to as “JNKs”) are membersof the mitogen-activated protein kinase (MAPK) family. JNKs are involvedin response to various stimuli, including proinflammatory cytokines andenvironmental stress. JNKs, and JNK3 in particular, play an importantrole during apoptotic death of cells and therefore have been implicatedin various disorders including stroke, traumatic brain injury and otherneurodegenerative diseases such as Parkinson disease, Alzheimer diseaseand others. Since JNK activity is a physiological regulator of AP-1transcriptional activity, JNK inhibitors are expected to reduceinflammatory response.

Apoptosis is a form of cell death in which the cell activelyparticipates in its own destruction in a process involving acharacteristic series of biochemical and morphological changes which areregulated by specific cell death genes. The apoptotic cell death is aprocess that has been observed in the developing mammalian nervoussystem. In mice, the inactivation by homologous recombination of genesthat encode proteins that promote apoptosis, such as the caspase-3 orthe Bax protein, prevents developmental neuronal cell death. Thedestruction of genes that encode cell death suppressors such as Bcl-x,leads to enhanced neuronal cell death. There is increasing evidence thatapoptosis plays an important role in the pathology of acute and chronicneurodegenerative diseases. For example, in transgenic miceoverexpressing the anti-apoptotic Bcl-2 protein in the nervous systemthere is a decrease in infarct volume following cerebral ischemia.Similarly, injection of the caspase inhibitor BAF reduces neuronal celldeath following hypoxia/ischaemia in neonatal rats. Another example isspinal muscular atrophy (a motor neurondisease) where loss of functionmutations in the SMN gene is associated with the disease. Recent datahas shown that the wild type SMN protein binds to Bcl-2 and co-operateswith it to inhibit apoptosis. These results suggest that inhibitors ofneuronal apoptosis could be beneficial in the treatment of humanneurodegenerative diseases. There is increasing evidence that neuronalapoptosis is an important pathological feature of stroke, traumaticbrain injury and other neurodegenerative diseases. Therefore,pharmacotherapy using inhibitors of neuronal apoptosis may provide atherapeutic benefit in neurodegenerative conditions.

A number of groups have studied the mechanisms of neuronal cell deathusing in vitro cell culture systems and the results suggest that in somesystems the transcription factor c-Jun is activated by the removal ofsurvival signals and promotes cell death.

Antibodies specific for c-Jun protected NGF-deprived rat sympatheticneurones from apoptosis. Analogous neuroprotection due to expression ofa c-Jun dominant negative mutant has been demonstrated, whereasoverexpression of wild type c-Jun protein was sufficient to induceapoptosis in the presence of NGF. Estus and co-workers recently showedthat an increase in c-Jun RNA levels occurs in cortical neuronesundergoing apoptosis after treatment with β-amyloid peptide (Estus etal., 1997, J. Neurosci. 17, 7736-7745). It has also been shown thatc-Jun is required for apoptosis in cerebellar granule neurones deprivedof survival signals.

c-Jun is activated by JNKs, which phosphorylate its transcriptionalactivation domain. In humans there are three JNK genes: JNK1, JNK2 andJNK3. The RNAs encoding JNK1 and JNK2 are expressed in many tissues,including the brain, but JNK3 is restricted to the nervous system and toa smaller extent the heart and testes.

JNKs are strongly activated in cellular responses to various stressessuch as UV radiation, heat shock, osmotic shock, DNA-damaging agents,and proinflammatory cytokines such as TNFα, IL-1β and others. Upstreamregulators of the JNK pathway include kinases such as SEK1, MKK7 andMEKK1. There is evidence that Jun kinase activity is required forneuronal apoptosis in vitro. Overexpression of MEKK1 in sympatheticneurones increased c-Jun protein levels and phosphorylation and inducedapoptosis in the presence of NGF indicating that activation of the Junkinase pathway can trigger neuronal cell death. The Jun kinase pathwayhas been shown to be necessary for the death of differentiated PC12cells deprived of NGF. Furthermore, compound CEP-1347, which inhibitsthe c-Jun pathway (upstream of Jun kinase), protects motor neuronesagainst cell death induced by survival factor withdrawal.

In JNK3 homozygous (−/−) knockout mice, epileptic seizures and death ofhippocampal CA3 neurones induced by injection of kainic acid is blocked.This indicates that JNK3 is involved in certain forms of neuronal celldeath in vivo. It is also a critical component of GluR6-mediatedexcitotoxicity. Furthermore, JNK3 (−/−) mice appear to develop normallyand are viable suggesting that JNK3 is not essential for development orviability.

Strong nuclear JNK3 immunoreactivity in the brain CA1 neurones ofpatients with acute hypoxia suggests that JNK3 is involved inhypoxia-related neurodegeneration. Transient hypoxia, may also triggerapoptosis through JNK signaling pathway in developing brain neurones.

Furthermore, JNK3 immunoreactivity is colocalized with Alzheimerdisease-affected neurones. Moreover JNK3 is related to neurofibrillarypathology of Alzheimer disease. In particular, JNK3 induces robustphosphorylation of amyloid precursor protein (APP) thus affecting itsmetabolism in disease state.

The present inventors have provided compounds which are inhibitors ofc-Jun N-terminal kinases.

The first aspect of the present invention relates to a compound offormula (I) as defined below:

wherein:

-   -   R stands for carbocyclyl, substituted carbocyclyl, heterocyclyl,        or substituted heterocyclyl, wherein        -   the optionally substituted carbocyclyl or optionally            substituted heterocyclyl group is optionally fused to an            unsaturated, partially unsaturated or fully saturated five            to seven membered ring containing zero to three heteroatoms,        -   each substitutable carbon atom in R, including the optional            fused ring, is optionally and independently substituted by            one or more of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, carbocyclyl, or            heterocyclyl, halogen, haloalkyl, OR², SR², NO₂, CN, NR²R²,            NR²COR², NR²CONR²R², NR²COR², NR²CO₂R², CO₂R², COR²,            CONR²R², S(O)₂R², SONH₂, S(O)R², SO₂NR²R², NR²S(O)₂R²,            wherein each R² may be the same or different and is as            defined below and wherein:            -   the C₁₋₁₂ alkyl optionally incorporates one or two                insertions selected from the group consisting of —O—,                —C(O)—, —N(R²)—, —S(O)— and —S(O₂)— wherein each R² may                be the same or different and is as defined below;            -   the C₁₋₁₂ alkyl, carbocyclyl, or heterocyclyl group is                optionally substituted by one or more of halogen,                haloalkyl, OR², SR², NO₂, CN, NR²R², NR²COR²,                NR²CONR²R², NR²COR², NR²CO₂R², CO₂R², COR², CONR² ₂,                S(O)₂R², SONH₂, S(O)R², SO₂NR²R², NR²S(O)₂R²; wherein                each R² may be the same or different and is as defined                below and            -   the carbocyclyl, or heterocyclyl group is optionally                substituted by one or more C₁₋₁₂ alkyl,        -   each saturated carbon in the optional fused ring is further            optionally and independently substituted by ═O, ═S, ═NNHR²,            NNR²R², ═N—OR², ═NNHCOR², ═NNHCO₂R², ═NNSO₂R², or ═NR²,            wherein each R² may be the same or different and is as            defined below; and        -   each substitutable nitrogen atom in R is optionally            substituted by R³, COR², SO₂R² or CO₂R², wherein each R² and            R³ may be the same or different and is as defined below;    -   R² is hydrogen, C₁₋₁₂ alkyl or aryl, optionally substituted by        one or more of C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, OR⁴, SR⁴,        NO₂, CN, NR⁴R⁴, NR⁴COR⁴, NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴CO₂R⁴, CO₂R⁴,        COR⁴, CONR⁴ ₂, S(O)₂R⁴, SONH₂, S(O)R⁴, SO₂ NR⁴R⁴, NR⁴S(O)₂R⁴,        wherein the C₁₋₁₂ alkyl group optionally incorporates one or two        insertions selected from the group consisting of —O—, —N(R⁴)—,        —S(O)— and —S(O₂)—, wherein each R⁴ may be the same or different        and is as defined below;    -   R³ is C₁₋₁₂ alkyl or aryl, optionally substituted by one or more        of C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, OR⁴, SR⁴, NO₂, CN,        NR⁴R⁴, NR⁴COR⁴, NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴CO₂R⁴, CO₂R⁴, COR⁴,        CONR⁴ ₂, S(O)₂R⁴, SONH₂, S(O)R⁴, SO₂ NR⁴R⁴, NR⁴S(O)₂R⁴, wherein        the C₁₋₁₂ alkyl group optionally incorporates one or two        insertions selected from the group consisting of —O—, —N(R⁴)—,        —S(O)— and —S(O₂)—, wherein each R⁴ may be the same or different        and is as defined below;    -   R⁴ is hydrogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl;    -   with the proviso that when R is phenyl substituted with branched        C₆-alkyl (—CH(CH₂—CH(CH₃)CH₃))—CH₂—) incorporating two        insertions —(CO)— and —NH—, the C₆-alkyl group is not        substituted with CN;        and the pharmaceutically acceptable salts, and other        pharmaceutically acceptable biohydrolyzable derivatives thereof,        including esters, amides, carbamates, carbonates, ureides,        solvates, hydrates, affinity reagents or prodrugs thereof.

For the avoidance of doubt, when a group as defined above contains twoor more radicals, e.g. the radical R², as for example in the groupsSO₂NR²R² and NR²COR², the radicals R² may be the same or different.

For the purposes of this invention, “alkyl” means a straight chain orbranched alkyl radical of 1 to 12 carbon atoms, preferably 1 to 6 carbonatoms and most preferably 1 to 4 carbon atoms including but not limitedto methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl etc. The term “alkenyl” means a straight chain or branchedalkylenyl radical of 2 to 12 carbon atoms, preferably 2 to 6 carbonatoms and most preferably 2 to 4 carbon atoms, and containing one ormore carbon-carbon double bonds and includes but is not limited toethylene, n-propyl-1-ene, n-propyl-2-ene, isopropylene, etc. The term“alkynyl” means a straight chain or branched alkynyl radical of 2 to 12carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2 to 4carbon atoms, and containing one or more carbon-carbon triple bonds andincludes but is not limited to ethynyl, 2-methylethynyl etc. The term“cycloalkyl” means an saturated or partly unsaturated 3-12 memberedcyclic alkyl group and includes but not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl etc. Cycloalkyl groups may beoptionally substituted or fused to one or more aryl, heterocyclyl orcycloalkyl group. “Heterocycloalkyl” means a 3-12 membered saturated orpartly unsaturated cycloalkyl containing one or more hetero atomselected from N, S and O. “Haloalkyl” means an alkyl radical substitutedwith one or more halide atoms for example CH₂CH₂Br, CF₃ or CCl₃.

“Carbocyclyl” relates to a saturated, partly unsaturated or unsaturated3-10 membered hydrocarbon ring, including cycloalkyl and aryl.

“Aryl” means an aromatic 3-10 membered hydrocarbon containing one ringor being fused to one or more saturated or unsaturated rings includingbut not limited to phenyl, napthyl, anthracenyl or phenanthracenyl.

“Heteroaryl” means an aromatic 3-10 membered aryl containing one or moreheteroatoms selected from N, O or S and containing one ring or beingfused to one or more saturated or unsaturated rings and.

“Heterocyclyl” means a 3-10 membered ring system containing one or moreheteroatoms selected from N, O or S and includes heteroaryl. Theheterocyclyl system can contain one ring or may be fused to one or moresaturated or unsaturated rings; the heterocyclyl can be fully saturated,partially saturated or unsaturated and includes but is not limitedheteroaryl and heterocarbocyclyl, e.g. cyclohexyl, phenyl, acridine,benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine,dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine,indole, indoline, indolizine, indazole, isoindole, isoquinoline,isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole,oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine,phenothiazine, phenoxazine, phthalazine, piperazine, piperidine,pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline,quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran,tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole,thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran,triazine, triazole, and trithiane.

Halogen means F, Cl, Br or I, preferably F.

R is preferably substituted with one or more of alkyl (e.g. methyl,ethyl or propyl), haloalkyl (preferably CF₃), halogen (e.g. F, Cl or Br,preferably F), OR⁸, SR⁸, SOR⁸, (NR⁸)₂, wherein R⁸ is independentlyselected from hydrogen, C₁₋₄ alkyl or haloalkyl and is preferably phenylor napthyl. When R is phenyl it is preferably substituted in the4-(para) position, e.g. by NR⁶ R⁶, where R⁶ stands independently for Hor C₁₋₄ alkyl.

Representative compounds according to the first aspect of the inventionare illustrated below.

The compounds of the invention may be provided as a salt, preferably asa pharmaceutically acceptable salt of compounds of formula (I). Examplesof pharmaceutically acceptable salts of these compounds include thosederived from organic acids such as acetic acid, malic acid, tartaricacid, citric acid, lactic acid, oxalic acid, succinic acid, fumaricacid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid,mandelic acid, methanesulphonic acid, benzenesulphonic acid andp-toluenesulphonic acid, mineral acids such as hydrochloric andsulphuric acid and the like, giving methanesulphonate,benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, andthe like, respectively or those derived from bases such as organic andinorganic bases. Examples of suitable inorganic bases for the formationof salts of compounds for this invention include the hydroxides,carbonates, and bicarbonates of ammonia, lithium, sodium, calcium,potassium, aluminium, iron, magnesium, zinc and the like. Salts can alsobe formed with suitable organic bases. Such bases suitable for theformation of pharmaceutically acceptable base addition salts withcompounds of the present invention include organic bases which arenontoxic and strong enough to form salts. Such organic bases are alreadywell known in the art and may include amino acids such as arginine andlysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, andtriethanolamine, choline, mono-, di-, and trialkylamines, such asmethylamine, dimethylamine, and trimethylamine, guanidine;N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine;N-benzylphenethylamine; tris(hydroxymethyl)aminomethane; and the like.

Salts may be prepared in a conventional manner using methods well knownin the art. Acid addition salts of said basic compounds may be preparedby dissolving the free base compounds according to the first or secondaspects of the invention in aqueous or aqueous alcohol solution or othersuitable solvents containing the required acid. Where a compound of theinvention contains an acidic function, a base salt of said compound maybe prepared by reacting said compound with a suitable base. The acid orbase salt may separate directly or can be obtained by concentrating thesolution e.g. by evaporation. The compounds of this invention may alsoexist in solvated or hydrated forms.

The invention also extends to a prodrug of the aforementioned compounds.A prodrug is any compound that may be converted under physiologicalconditions or by solvolysis to any of the compounds of the invention orto a pharmaceutically acceptable salt of the compounds of the invention.A prodrug may be inactive when administered to a subject but isconverted in vivo to an active compound of the invention.

The compounds of the invention may contain one or more asymmetric carbonatoms and may exist in racemic and optically active forms. The firstaspect of the invention covers all of these compounds.

In accordance with the second aspect of the present invention, thecompound of the general formula (I):

can be made by hydrogenating a compound of the general formula (II):

in which R is as defined above and hal stands for a halogen atom,principally F or Cl, e.g. using in the presence of a suitable metalcatalyst, such as e.g. palladium on activated carbon, and suitable aminesuch as e.g. triethylamine. The reaction can be run using a solution ofcompound (II) in a single solvent (e.g. alcohol, such as methanol orethanol) or a mixture of solvents including e.g. an alcohol,dichloromethane, chloroform, etc.

The compound of the general formula (II) can be made by halogenating acompound of the general formula (III) in the 2 position, e.g.:

where R is as defined above, e.g. using P(O)Cl₃ at elevated temperature(about 100° C.).

The compound of the general formula (III) can be made from 7-azaindoleaccording to processes known in the art, see for example Glennon, K. C.et al. (WO00/56710) and Viaud, M.-C. et al. (EP0737685) and Cheung, M.et al. (WO99/21859). An example of a suitable scheme for the productionof the compound of the general formula (III) is:

The third aspect of the present invention provides a compositioncomprising a compound of the general formula (I) as defined above incombination with a pharmaceutically acceptable carrier, diluent orexcipient.

The composition may also comprise one or more additional active agent,such as an anti-inflammatory agent (for example a p38 inhibitor,glutamate receptor antagonist, or a calcium channel antagonist), achemotherapeutic agent and/or an antiproliferative agent.

Suitable carriers and/or diluents are well known in the art and includepharmaceutical grade starch, mannitol, lactose, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, (or other sugar),magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers orwater (preferably sterile). The composition may be a mixed preparationof a composition or may be a combined preparation for simultaneous,separate or sequential use (including administration).

The composition according to the invention for use in the aforementionedindications may be administered by any convenient method, for example byoral (including by inhalation), parenteral, mucosal (e.g. buccal,sublingual, nasal), rectal or transdermal administration and thecompositions adapted accordingly.

For oral administration, the composition can be formulated as liquids orsolids, for example solutions, syrups, suspensions or emulsions,tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or physiologically acceptable salt in a suitable aqueousor non-aqueous liquid carrier(s) for example water, ethanol, glycerine,polyethylene glycol or an oil. The formulation may also contain asuspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and microcrystalline cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, powders, granules or pelletscontaining the active ingredient can be prepared using standard carriersand then filled into a hard gelatin capsule; alternatively, a dispersionor suspension can be prepared using any suitable pharmaceuticalcarrier(s), for example aqueous gums, celluloses, silicates or oils andthe dispersion or suspension then filled into a soft gelatin capsule.

Compositions for oral administration may be designed to protect theactive ingredient against degradation as it passes through thealimentary tract, for example by an outer coating of the formulation ona tablet or capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or physiologically acceptable salt in a sterile aqueous ornon-aqueous carrier or parenterally acceptable oil, for examplepolyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil orsesame oil. Alternatively, the solution can be lyophilised and thenreconstituted with a suitable solvent just prior to administration.

Compositions for nasal or oral administration may conveniently beformulated as aerosols, drops, gels and powders. Aerosol formulationstypically comprise a solution or fine suspension of the active substancein a physiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apharmaceutically acceptable propellant. The aerosol dosage forms canalso take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal or vaginal administration are conveniently inthe form of suppositories (containing a conventional suppository basesuch as cocoa butter), pessaries, vaginal tabs, foams or enemas.

Compositions suitable for transdermal administration include ointments,gels, patches and injections including powder injections.

Conveniently the composition is in unit dose form such as a tablet,capsule or ampoule.

In addition, the present invention provides a process for themanufacture of a composition according to the invention, as describedabove. The manufacture can be carried out by standard techniques wellknown in the art and involves combining a compound according to thefirst aspect of the invention and the pharmaceutically acceptablecarrier or diluent. The composition may be in any form including atablet, a liquid, a capsule, and a powder or in the form of a foodproduct, e.g. a functional food. In the latter case the food productitself may act as the pharmaceutically acceptable carrier.

The present invention provides a compound of the first aspect or acomposition of the third aspect for use in therapy/medicine.

The fourth aspect of the present invention relates to a compound of thegeneral formula I as defined below

or a composition containing the compound, for use in inhibiting JNKwherein:

-   -   R stands for carbocyclyl, substituted carbocyclyl, heterocyclyl,        or substituted heterocyclyl, wherein        -   the optionally substituted carbocyclyl or optionally            substituted heterocyclyl group is optionally fused to an            unsaturated, partially unsaturated or fully saturated five            to seven membered ring containing zero to three heteroatoms,        -   each substitutable carbon atom in R, including the optional            fused ring, is optionally and independently substituted by            one or more of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, carbocyclyl, or            heterocyclyl, halogen, haloalkyl, OR², SR², NO₂, CN, NR²R²,            NR²COR², NR²CONR²R², NR²COR², NR²CO₂R², CO₂R², COR²,            CONR²R², S(O)₂R², SONH₂, S(O)R², SO₂NR²R², NR²S(O)₂R²,            wherein each R² may be the same or different and is as            defined below and wherein:            -   the C₁₋₁₂ alkyl optionally incorporates one or two                insertions selected from the group consisting of —O—,                —C(O)—, —N(R²)—, —S(O)— and —S(O₂)— wherein each R² may                be the same or different and is as defined below;            -   the C₁₋₁₂ alkyl, carbocyclyl, or heterocyclyl group is                optionally substituted by one or more of halogen,                haloalkyl, OR², SR², NO₂, CN, NR²R², NR²COR²,                NR²CONR²R², NR²COR², NR²CO₂R², CO₂R², COR², CONR² ₂,                S(O)₂R², SONH₂, S(O)R², SO₂NR²R², NR²S(O)₂R²; wherein                each R² may be the same or different and is as defined                below and            -   the carbocyclyl, or heterocyclyl group is optionally                substituted by one or more C₁₋₁₂ alkyl,        -   each saturated carbon in the optional fused ring is further            optionally and independently substituted by ═O, ═S, ═NNHR²,            NNR²R², ═N—OR², ═NNHCOR², ═NNHCO₂R², ═NNSO₂R², or ═NR²,            wherein each R² may be the same or different and is as            defined below; and        -   each substitutable nitrogen atom in R is optionally            substituted by R³, COR², SO₂R² or CO₂R², wherein each R² and            R³ may be the same or different and is as defined below;    -   R² is hydrogen, C₁₋₁₂ alkyl or aryl, optionally substituted by        one or more of C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, OR⁴, SR⁴,        NO₂, CN, NR⁴R⁴, NR⁴COR⁴, NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴CO₂R⁴, CO₂R⁴,        COR⁴, CONR⁴ ₂, S(O)₂R⁴, SONH₂, S(O)R⁴, SO₂ NR⁴R⁴, NR⁴S(O)₂R⁴,        wherein the C₁₋₂ alkyl group optionally incorporates one or two        insertions selected from the group consisting of —O—, —N(R⁴)—,        —S(O)— and —S(O₂)—, wherein each R⁴ may be the same or different        and is as defined below;    -   R³ is C₁₋₁₂ alkyl or aryl, optionally substituted by one or more        of C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, OR⁴, SR⁴, NO₂, CN,        NR⁴R⁴, NR⁴COR⁴, NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴CO₂R⁴, CO₂R⁴, COR⁴,        CONR⁴ ₂, S(O)₂R⁴, SONH₂, S(O)R⁴, SO₂ NR⁴R⁴, NR⁴S(O)₂R⁴, wherein        the C₁₋₁₂ alkyl group optionally incorporates one or two        insertions selected from the group consisting of —O—, —N(R⁴)—,        —S(O)— and —S(O₂)—, wherein each R⁴ may be the same or different        and is as defined below;    -   R⁴ is hydrogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl;        and the pharmaceutically acceptable salts, and other        pharmaceutically acceptable biohydrolyzable derivatives thereof,        including esters, amides, carbamates, carbonates, ureides,        solvates, hydrates, affinity reagents or prodrugs thereof.

All preferred options for R, R², R³ and R⁴ and any substitutions orinsertions thereof are as set out in the first aspect of the presentinvention. Preferred features of the composition of the fourth aspectare set out in the third aspect.

The compounds of the fourth aspect of the present invention areinhibitors of JNK, such as JNK1, JNK2, or JNK3. In particular, thecompounds of the present invention are inhibitors of JNK3. Preferably,the compounds of the present invention inhibit JNK3 specifically.

One advantage of the compounds of the present invention is that theyshow a good stability to liver microsomes, at least when tested in vitroand hence are are not rapidly metabolically removed from the body.

The compounds are therefore useful for conditions for which inhibitionof JNK activity is beneficial. Thus, preferably, this aspect provides acompound of the general formula (I), or a composition containing acompound of formula (I) as defined in the fourth aspect of the presentinvention, as described above, for the prevention or treatment of aJNK-mediated disorder. The compounds of the general formula I may thusbe used for the inhibition of JNK, more preferably for the inhibition ofJNK3.

A “JNK-mediated disorder” is any disease or deleterious condition inwhich JNK plays a role. Examples include neurodegenerative disorder(including dementia), inflammatory disease, a disorder linked toapoptosis, particularly neuronal apoptosis, autoimmune disease,destructive bone disorder, proliferative disorder, cancer, infectiousdisease, allergy, ischemia reperfusion injury, heart attack, angiogenicdisorder, organ hypoxia, vascular hyperplasia, cardiac hypertrophy,thrombin induced platelet aggregation and any condition associated withprostaglandin endoperoxidase synthase-2. The compounds of the presentinvention may be used for any of these JNK-mediated disorders.

The compounds of the fourth aspect of the present invention areparticularly useful for the prevention or treatment of aneurodegenerative disorder. In particular, the neurodegenerativedisorder results from apoptosis and/or inflammation. Examples ofneurodegenerative disorders are: dementia; Alzheimer's disease;Parkinson's disease; Amyotrophic Lateral Sclerosis; Huntington'sdisease; senile chorea; Sydenham's chorea; hypoglycemia; head and spinalcord trauma including traumatic head injury; acute and chronic pain;epilepsy and seizures; olivopontocerebellar dementia; neuronal celldeath; hypoxia-related neurodegeneration; acute hypoxia; glutamatetoxicity including glutamate neurotoxicity; cerebral ischemia; dementialinked to meningitis and/or neurosis; cerebrovascular dementia; ordementia in an HIV-infected patient.

The neurodegenerative disorder may be a peripheral neuropathy, includingmononeuropathy, multiple mononeuropathy or polyneuropathy. Examples ofperipheral neuropathy may be found in diabetes mellitus, Lyme disease oruremia; peripheral neuropathy caused by a toxic agent; demyelinatingdisease such as acute or chronic inflammatory polyneuropathy,leukodystrophies, or Guillain-Barré syndrome; multiple mononeuropathysecondary to a collagen vascular disorder (e.g. polyarteritis nodosa,SLE, Sjögren's syndrome); multiple mononeuropathy secondary tosarcoidosis; multiple mononeuropathy secondary to a metabolic disease(e.g. diabetes or amyloidosis); or multiple mononeuropathy secondary toan infectious disease (e.g. Lyme disease or HIV infection).

The compounds of the invention can also be used to prevent or treatdisorders resulting from inflammation. These include, for example,inflammatory bowel disorder, bronchitis, asthma, acute pancreatitis,chronic pancreatitis, allergies of various types, and possiblyAlzheimer's disease. Autoimmune diseases which may also be treated orprevented by the compounds of the present invention include rheumatoidarthritis, systemic lupus erythematosus, glumerulonephritis,scleroderma, chronic thyroiditis, Graves's disease, autoimmunegastritis, diabetes, autoimmune haemolytis anaemia, autoimmuneneutropaenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myastlhenia gravis, multiple sclerosis, ulcerative colitis,Crohn's disease, psoriasis or graft vs host disease.

A compound of the present invention may be administered simultaneously,subsequently or sequentially with one or more other active agent, suchas an anti-inflammatory agent e.g. p38 inhibitor, glutamate receptorantagonist, calcium channel antagonist, a chemotherapeutic agent or anantiproliferative agent. For example, for acute treatment, a p38inhibitor may be administered to a patient prior to administering acompound of the present invention.

The compounds of the invention will normally be administered in a dailydosage regimen (for an adult patient) of, for example, an oral dose ofbetween 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, e.g.between 10 and 250 mg or an intravenous, subcutaneous, or intramusculardose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg,e.g. between 1 and 25 mg of the compound of the formula (I) or aphysiologically acceptable salt thereof calculated as the free base, thecompound being administered 1 to 4 times per day. Suitably the compoundswill be administered for a period of continuous therapy, for example fora week or more.

Accordingly the fifth aspect of the present invention relates to amethod of treating or preventing a JNK-mediated disorder in anindividual, which method comprises administering to said individual acompound as defined in the fourth aspect or a composition containingthat compound. The active compound is preferably administered in acumulative effective amount. The individual may be in need of thetreatment or prevention. Any of the JNK-mediated disorders listed abovein relation to the fourth aspect may be the subject of treatment orprevention according to the fifth aspect. One or more other active agentmay be administered to the individual simultaneously, subsequently orsequentially to administering the compound. The other active agent maybe an anti-inflammatory agent such as a p38 inhibitor, glutamatereceptor antagonist, calcium channel antagonist, a chemotherapeuticagent or an antiproliferative agent, but is preferably p38 inhibitor foracute treatment.

The sixth aspect of the present invention provides the use of a compoundof the general formula (I) as defined in the fourth aspect of theinvention in the manufacture of a medicament for the prevention ortreatment of a JNK-mediated disorder. The medicament may be used fortreatment or prevention of any of the JNK-mediated disorders listedabove in relation to the fourth aspect. Again, the compound of thepresent invention may be administered simultaneously, subsequently orsequentially with one or more other active agent, preferably a p38inhibitor for acute treatment.

According to the seventh aspect of the present invention, there is alsoprovided an assay for determining the activity of the compounds of thepresent invention, comprising providing a system for assaying theactivity and assaying the activity of the compound. Preferably the assayis for the INK inhibiting activity of the compound, more preferably itis for the JNK3-specific inhibiting activity of the compounds. Thecompounds of the invention may be assayed in vitro, in vivo, in silico,or in a primary cell culture or a cell line. In vitro assays includeassays that determine inhibition of either the kinase activity or ATPaseactivity of activated JNK. Alternatively, in vitro assays may quantitatethe ability of a compound to bind JNK and may be measured either byradiolabelling the compound prior to binding, then isolating theinhibitor/JNK complex and determining the amount of the radiolabel boundor by running a competition experiment where new inhibitors areincubated with JNK bound to known radioligands. An example of an assaywhich may be used is Scintillation Proximity Assay (SPA), preferablyusing radiolabelled ATP. Another example is ELISA. Any type or isoformof JNK may be used in these assays.

In a yet further aspect of the present invention, there is provided amethod of inhibiting the activity or function of a JNK, particularlyJNK3, which method comprises exposing a JNK to a compound or acomposition of the first or fourth aspect of the present invention. Themethod may be performed in a research model, in vitro, in silico, or invivo such as in an animal model. A suitable animal model may be a kainicacid model in rat or mice, traumatic brain injury model in rat, or MPTPin mice.

All features of each of the aspects apply to all other aspects mutatismutandis.

Below, the present invention is illustrated using non-limiting examples.

EXAMPLES Synthesis of Example 5-substituted 7-azaindole Derivative 7

3,3-Dibromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (2)

Technical (90%) pyridinium tribromide (220.4 g, 0.62 mol) was addedportionwise over a period of 30 min to a stirred suspension of7-azaindole (1, 27.13 g, 0.23 mol) in t-BuOH (1.36 L). The mixture wasstirred at r.t for 3 h, and more pyridinium tribromide (73.3 g, 0.21mol) was added in one portion. After additional stirring at r.t. for 2h, the solvent was evaporated under reduced pressure. The residue wasseparated between water:AcOEt=1:1 (4.2 L). The aqueous layer wasextracted with AcOEt (2×800 mL). Combined organic solutions were washedwith water (2×500 mL), brine, dried (MgSO₄) and concentrated to dynessin vacuum. The residue was triturated with CH₂Cl₂ (1500 mL) for 20 min.The solid was filtered off, washed with CH₂Cl₂ (250 mL) and dried invacuum to afford 2 (49.85 g, 75%) as yellow powder. ¹H NMR (400 MHz,DMSO-d₆) δ 7.16 (dd, J=7.4, 5.1 Hz, 1H), 7.98 (dd, J=7.4, 1.5 Hz, 1H),8.19 (dd, J=5.1, 1.5 Hz, 1H), 11.97 (bs, 1H).

3,3,5-Tribromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (3)

Bromine (13.4 mL, 0.262 mol) was added dropwise over a period of 30 minto a cooled (ice bath) and stirred suspension of 2 (37.86 g, 0.131 mol)in water:t-BuOH=1:1 (1500 mL). Cooling bath was removed and the mixturewas stirred at r.t. overnight. Then the solution was cooled to 15° C.and saturated aqueous solution of NaHCO₃ (278 mL) was added. A yellowsuspension, which was formed, was concentrated in vacuum (bathtemperature<32° C.) until about 1000 mL of condensate was collected. Thesolid was filtered off, washed with water (200 mL), and dried in vacuumto afford 3 (40.85 g, 85%) as tan powder.

5-Bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (4)

Zinc dust (34.0 g, 0.52 mol) was added in small portion to a stirredsuspension of 3 (40.85 g, 0.111 mol) in glacial acetic acid (1000 mL) atsuch a rate that the temperature was maintained between 20-25° C.(strongly exothermic reaction; external ice bath cooling). Addition tookabout 20 min. Cooling bath was removed and stirring was continued atr.t. for 2 h. The solid was filtered off, washed with toluene (50 mL)and triturated with CH₂Cl₂:MeOH=4:1 (2.5 L). The solution was decantedoff and treated with 1.0 M aqueous Na₂CO₃ solution (170 mL). Afterstirring for 1 h the two layers were separated. The organic layer waswashed again with 1.0 M aqueous Na₂CO₃ solution (50 mL). The combinedaqueous layers were extracted with CH₂Cl₂:MeOH=4:1 (10×100 mL). Combinedorganic solutions were dried with MgSO₄ (200 g) and concentrated. Theresidual solid was dissolved in THF (2000 mL) and insoluble material wasfiltered off. The filtrate was concentrated to dryness in vacuum toafford 4 (16.93 g, 72%) as tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 3.57(s, 2H), 7.75 (m, 1H), 8.14 (m, 1H), 11.13 (bs, 1H).

5-(3-Fluoro-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (5)

A mixture of 4 (16.63 g, 78.5 mmol), 3-fluorophenylboronic acid (16.47g, 117.7 mmol), Pd(PPh₃)₂Cl₂ (2.73 g, 6.60 mmol), LiCl (9.95 g, 0.23mol), 1.0 M aqueous Na₂CO₃ solution (196 mL, 0.196 mol) in EtOH (470mL)—toluene (470 mL) was refluxed overnight. More Pd(PPh₃)₂Cl₂ (1.30 g,3.14 mmol) was added and reflux was continued for 24 h. The mixture wascooled, and the organic layer was separated and washed with brine (100mL). The washings were combined with the aqueous layer and extractedwith AcOEt (4×400 mL). Combined extracts were washed with brine, addedto the organic layer and dried with MgSO₄. The solution was concentratedto dryness in vacuum to give 26.98 g of brown semisolid, which wastriturated with ether:hexane=1:1 (2×500 mL). The residue was dried invacuum to afford 5 (16.85 g, 94%) as tan solid, which was used in thenext step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 3.66(s, 2H), 7.08 (dddd, J=8.4, 8.2, 2.4, 0.9 Hz, 1H), 7.22 (ddd, J=10.0,2.4, 1.7 Hz, 1H), 7.30 (ddd, J=8.1, 1.7, 0.9 Hz, 1H), 7.43 (ddd, J=8.2,8.1, 6.0 Hz, 1H), 7.69 (s, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.98 (bs, 1H).

2-Chloro-5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine (6)

A suspension of 5 (16.52 g, 72.4 mmol) in neat P(O)Cl₃ (21.5 mL, 0.231mol) was stirred at 100-105° C. for 4 h. The mixture was then cooled tor.t., diluted with p-xylene (100 mL) and concentrated to dryness invacuum. The residue was separated between saturated aqueousNaHCO₃—AcOEt. 10% aqueous solution of Na₂CO₃ was added to basify theaqueous layer to pH 9. Organic phase was separated and the aqueous layerwas extracted with AcOEt (8×300 mL). Combined organic solutions weredried MgSO₄, concentrated, and the residue was purified by silicagelchromatography (SGC) using CH₂Cl₂:AcOEt as eluent in gradient to affordrecovered starting material 5 (0.76 g, 5%). The desired product was thencrystallized from acetone to afford 6 (10.06 g, 56%), thin tan needles.¹H NMR (400 MHz, CDCl₃) δ 6.47 (s, 1H), 7.08 (tdd, J=8.1, 2.3, 1.5 Hz,1H), 7.33 (ddd, J=9.9, 2.3, 1.6 Hz, 1H), 7.38-7.48 (m, 2H), 8.03 (d,J=2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 11.46 (bs, 1H).

5-(3-Fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine (7)

A mixture of chloride 6 (5.23 g, 21.3 mmol), 10% Pd/C (2.7 g), Et₃N (3.6mL, 25.8 mmol) in THF:MeOH=5:1 (180 mL) was stirred under H₂ overnight.More 10% Pd/C (1.3 g) was added and stirring was continued for 3 h.Catalyst was removed by filtration and the solution was concentrated todryness in vacuum. The residue was purified by SGC with CH₂Cl₂:AcOEt aseluent in gradient (up to 20% AcOEt) to afford 7 (5.23 g, 88%), greenishpowder. ¹H NMR (400 MHz, CDCl₃) δ 6.59 (dd, J=3.5, 2.0 Hz, 1H),7.04-7.10 (m, 1H), 7.33-7.37 (m, 1H), 7.40-7.48 (m, 3H), 8.14 (d, J=2.1Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 9.91 (bs, 1H).

JNK1, JNK2, JNK3—SPA Assay

A typical assay for testing the activity of compounds to inhibit JNK1,JNK2 and JNK3 enzymes is as follows:

-   -   1. Compound is dissolved in DMSO to a convenient concentration        and this is diluted in 10% DMSO to a five times concentrate of        the desired starting concentration (frequently 1:100).    -   2. 10 μl of 500 mM EDTA is added to alternative wells of the        Opti-plate row, which will receive kinase reaction plus DMSO.        This creates the negative control.    -   3. For the JNK2 and JNK3 assay, compounds are prepared in six        2-fold dilutions with water and each concentration is tested in        duplicate. For the JNK1 assay compounds are prepared in four        5-fold dilutions with water which are tested in triplicate.        Controls are treated identically.    -   4. 20 μl per well of each compound concentration is transferred        to an Opti-plate, in duplicate.    -   5. 30 μl (JNK2/3 SPA) or 50 μl (JNK1 SPA) of substrate solution        (25 mM HEPES pH 7.5, 10 mM magnesium acetate with 3.33 μM ATP        (JNK2/3) or 2 μM ATP (JNK1), approximately 7.5 kBq [γ-33P] ATP,        GST-c-Jun, in water) is added to each well.    -   6. 50 μl (JNK2/3 SPA) or 30 μl (JNK1 SPA) of kinase solution        (JNK in 25 mM HEPES pH 7.5, 10 mM Mg Acetate) is added to each        well.

Kinase Kinase per well (μg) GST-c-Jun per well (μg) JNK1 0.25 1 JNK2 0.21.2 JNK3 0.16 1.2

-   -   7. The plate is incubated for 30 minutes at room temperature.    -   8. 100 μl of bead/stop solution is added to each well (5 mg/ml        glutathione-PVT-SPA beads, 40 mM ATP in PBS).    -   9. Plates are sealed and incubated for 30 minutes at room        temperature, centrifuged for 10 minutes at 2500 g and counted.    -   10. The IC₅₀ values are calculated as the concentration of the        compound being tested at which the phosphorylation of c-Jun is        decreased to 50% of the control value. Example IC₅₀ values for        the compounds of this invention are given in Table 1.

Examples of Inhibitory Potency Against JNK3 Kinase

TABLE 1 IC₅₀ values for selected compounds against JNK3 kinase CompoundJNK3 Number Structure IC₅₀ (μM) 1

1.2 2

<0.5

1. A compound of formula (I) as defined below:

wherein: R stands for carbocyclyl, substituted carbocyclyl, wherein theoptionally substituted carbocyclyl group is optionally fused to anunsaturated, partially unsaturated or fully saturated five to sevenmembered ring, each substitutable carbon atom in R, including theoptional fused ring, is optionally and independently substituted by oneor more of C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, carbocyclyl, or heterocyclyl,halogen, haloalkyl, OR², SR², NO₂, CN, NR²R², NR²COR², NR²CONR²R²,NR²COR², NR²CO₂R², CO₂R², COR², CONR²R², S(O)₂R², SONH₂, S(O)R²,SO₂NR²R², NR²S(O)₂R², wherein each R² may be the same or different andis as defined below and wherein: the C₁₋₁₂ alkyl optionally incorporatesone or two insertions selected from the group consisting of —O—, —C(O)—,—N(R²)—, —S(O)— and —S(O₂)— wherein each R² may be the same or differentand is as defined below; the C₁₋₁₂ alkyl, carbocyclyl, or heterocyclylgroup is optionally substituted by one or more of halogen, haloalkyl,OR², SR², NO₂, CN, NR²R², NR²COR², NR²CONR²R², NR²COR², NR²CO₂R², CO₂R²,COR², CONR² ₂, S(O)₂R², SONH₂, S(O)R², SO₂NR²R², NR²S(O)₂R²; whereineach R² may be the same or different and is as defined below and thecarbocyclyl, or heterocyclyl group is optionally substituted by one ormore C₁₋₁₂ alkyl, each saturated carbon in the optional fused ring isfurther optionally and independently substituted by ═O, ═S, ═NNHR²,NNR²R², ═N—OR², ═NNHCOR², ═NNHCO₂R², ═NNSO₂R², or ═NR², wherein each R²may be the same or different and is as defined below; and eachsubstitutable nitrogen atom in R is optionally substituted by R³, COR²,SO₂R² or CO₂R², wherein each R² and R³ may be the same or different andis as defined below; R² is hydrogen, C₁₋₁₂ alkyl or aryl, optionallysubstituted by one or more of C₁₋₄ alkyl, halogen, C₁₋₄ haloalkyl, OR⁴,SR⁴, NO₂, CN, NR⁴R⁴, NR⁴COR⁴, NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴CO₂R⁴, CO₂R⁴,COR⁴, CONR⁴ ₂, S(O)₂R⁴, SONH₂, S(O)R⁴, SO₂ NR⁴R⁴, NR⁴S(O)₂R⁴, whereinthe C₁₋₁₂ alkyl group optionally incorporates one or two insertionsselected from the group consisting of —O—, —N(R⁴)—, —S(O)— and —S(O₂)—,wherein each R⁴ may be the same or different and is as defined below; R³is C₁₋₁₂ alkyl or aryl, optionally substituted by one or more of C₁₋₄alkyl, halogen, C₁₋₄ haloalkyl, OR⁴, SR⁴, NO₂, CN, NR⁴R⁴, NR⁴COR⁴,NR⁴CONR⁴R⁴, NR⁴COR⁴, NR⁴CO₂R⁴, CO₂R⁴, COR⁴, CONR⁴ ₂, S(O)₂R⁴, SONH₂,S(O)R⁴, SO₂ NR⁴R⁴, NR⁴S(O)₂R⁴, wherein the C₁₋₁₂ alkyl group optionallyincorporates one or two insertions selected from the group consisting of—O—, —N(R⁴)—, —S(O)— and —S(O₂)—, wherein each R⁴ may be the same ordifferent and is as defined below; R⁴ is hydrogen, C₁₋₄ alkyl, or C₁₋₄haloalkyl; with the proviso that when R is phenyl substituted withbranched C₆-alkyl (—CH(CH₂—CH(CH₃)(CH₃))—CH₂—) incorporating twoinsertions —(CO)— and —NH—, the C₆-alkyl group is not substituted with—CN; and the pharmaceutically acceptable salts thereof.
 2. A compound asclaimed in claim 1, wherein R is an aryl, optionally substituted withone or more of alkyl, haloalkyl, halogen, OR⁸, S R⁸, SO R⁸, (NR⁸)₂,wherein R⁸ is independently selected from hydrogen, C₁₋₄ alkyl orhaloalkyl.
 3. A compound as claimed in claim 1, wherein R is anoptionally substituted aryl.
 4. A compound as claimed in claim 3,wherein R is phenyl substituted in the 4-(para) position.
 5. A compoundas claimed in claim 4, wherein R is phenyl substituted by NR⁶R⁶; andwherein each R⁶ is independently H or C₁₋₄ alkyl.
 6. A compound asclaimed in claim 3, wherein R is aryl substituted with F, Cl, Br,haloalkyl, or alkyl.
 7. A compound as claimed in claim 1, wherein thecompound is selected from the group consisting of:


8. A process for the manufacture of the compounds of claim 1 whichcomprises hydrogenating a compound of the general formula (II):

wherein R is as defined in claim 1 and hal stands for a halogen atom. 9.A process as claimed in claim 8, wherein the compound of the generalformula (II) is made by halogenating a compound of the general formula(III) in the 2 position

where R is as defined above and hal stands for halogen.
 10. Apharmaceutical formulation comprising a compound as defined in claim 1and a pharmaceutically acceptable carrier, diluent or excipient.
 11. Thecompound of claim 3, wherein R is selected from the group consisting ofphenyl and naphthyl.
 12. The compound of claim 6, wherein R is arylsubstituted with fluorine.
 13. The compound of claim 6, wherein thehaloalkyl is CF₃.
 14. The compound of claim 6, wherein the alkyl isselected from the group consisting of methyl, ethyl, and propyl.